PROJECT SUMMARY Angioplasty and stenting for Peripheral Arterial Disease (PAD) of the femoropopliteal artery (FPA) carries one of the highest rates of reconstruction failure because the FPA experiences low blood flow and large deformations during flexion of the limbs. Our results using perfused human cadaver models and PAD patients demonstrate that these deformations are significantly more severe than assumed previously, and that none of the existing PAD stents are able to adequately accommodate them, resulting in adverse stent-artery interactions that contribute to treatment failure. Informed by the mechanical and structural characteristics of human FPAs determined by studying >900 human arteries of different ages with different risk factors, and utilizing knowledge gained from studying 12 different commercial PAD stents, we propose to focus the current project on translating the results we obtained using human cadaver models to patients, and testing the hypothesis that a new optimized stent design capable of withstanding the severe biomechanical environment of the flexing limbs improves arterial healing. We will accomplish this through three Specific Aims. In Aim 1 we will validate cadaveric limb flexion-induced deformations using bent-limb patient CTAs at baseline and at 9 and 18 months after stenting. These data will allow us to translate results previously obtained using human cadavers to PAD patients, and to validate the ability of our computational models to predict location and severity of restenosis as a function of patient, lesion, and stent characteristics. In Aim 2 we will develop and manufacture optimized and generic stents for the FPA that would be able to accommodate limb flexion induced deformations while maintaining low intramural stresses and optimal hemodynamics. These stents will then be manufactured and evaluated in silico and in vitro in comparison with existing commercial devices. Finally, in Aim 3 we will compare optimal, generic, and commercial stents in a preclinical swine model of limb flexion, where performance of our optimized stent design will be compared to the generic design, and to one of the most commonly used commercial stents (Zilver) implanted in the popliteal artery. Validation of cadaveric FPA deformations in live PAD patients, and design of an optimized lower extremity stent may facilitate more durable reconstructions benefiting PAD patients with claudication and critical limb ischemia. Our extensive knowledge of FPA biomechanics and mechanobiology combined with deep understanding of commercial stent designs and computational models of limb flexion-induced deformations, will ensure successful completion of the new Aims, and will promote cost-effective in silico comparative effectiveness studies of current and future cardiovascular devices, helping advance the paradigm of patient-specific modeling and personalized medicine.